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The Menopause

The Menopause. Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill. Objectives. Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause

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The Menopause

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  1. The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill

  2. Objectives • Understand reproductive aging • Physiology • Stages • Understand the physiologic changes and symptoms associated with menopause • Discuss treatment options for conditions associated with menopause • Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin

  3. Reproductive Aging • Decline in reproductive potential • Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause • Due to ovarian aging (physiology) • Progresses with the decline in oocyte/follicular pool

  4. Reproductive Aging Oocytes and Follicles • Process begins in embryonic life. • 20 weeks gestation - 6 - 7 million follicles. • At birth - 1.5-2 million follicles • At menarche - 300,000- 400,000 follicles • Follicular atresia continues throughout life. • Follicular loss accelerates when the total number of follicles is ~25,000 • When follicles are sufficiently depleted (<1000), menopause occurs.

  5. Reproductive Aging Hormonal Changes Hypothalmus GnRH FSH Inhibin B + Normal Ovary Ovary

  6. Reproductive Aging Hormonal Changes Hypothalmus GnRH FSH Estradiol / Inhibin B + Aging Ovary Ovary

  7. Reproductive Aging Hormonal Changes

  8. Reproductive Aging Hormonal Changes Hypothalmus GnRH FSH Estradiol / Inhibin B + Menopausal Ovary Ovary

  9. Stages of Reproductive Aging

  10. Reproductive Stage Miscarriage Rate / month 25% 12% Pregnancy Rate / month 20 30 37 40 45 Age in years

  11. Stages of Reproductive Aging

  12. Perimenopause • Follows period of declining fertility • Precedes menopause • Characterized by • cycle irregularity (shortening then lengthening) • increasing symptoms • Duration 2 to 8 years (average 5 years)

  13. Diagnosing Perimenopause • Clinical diagnosis based on menstrual cycle pattern. • Early follicular phase FSH and symptoms may help solidify diagnosis. • Rule out hypothyroidism, depression etc.

  14. Perimenopause -- Symptoms: Highly Variable • Vasomotor instability (85%) • Sleep disturbances • Mood disturbances. • Somatic symptoms: • Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. • Oligo-  Anovulation • heavier or irregular cycles.

  15. Managing Perimenopause Goals: • Patient education • Prevention of endometrial cancer • Individualized symptomatic relief • Menstrual control • Minimizing hot flashes • Mood disturbances

  16. Managing Perimenopause

  17. Menopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887.

  18. Menopause • Marks the end of reproductive life • Cessation of menses for 12 months • Clinical diagnosis (not labs) • Result of egg depletion and estrogen production by the ovary due to…. • Natural aging or surgery

  19. Menopause Facts • Average age at menopause: 51 years • (1% at age 40, 5% after age 55) • Factors impacting age at menopause • Maternal age at menopause • Tobacco use • SES/ Education • Alcohol use • Body Mass Index • Factors that probably don’t impact on age at menopause • OCP use • Parity • Race • Height

  20. Menopause Age (years) Age at menopause 1850 1940 2000 Date *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at:http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02.US Department of Health and Human Services. Healthy People 2010. Washington, DC: January

  21. Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenitaltract Summary of Key Physical Changes • Vasomotor instability • Metabolic Changes • Coronary Artery Disease • Accelerated bone loss • Skin changes • Urogenital atrophy • Cognition (?) • Libido (?) Skin Bone

  22. Hot Flushes (aka Hot Flashes) • “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” • Number 1 complaint to physicians • Few seconds to several minutes • Rare to recurrent every few minutes • Most severe at night and during times of stress • More common among overweight women • Usually last for 1-2 years • 25% will last for more than 5 years

  23. Managing Hot Flushes/Flashes • Set realistic goals! • Lower the ambient temperature • Estrogen (80-95% reduction) • Alternative therapies • High dose progestins • Tibolone • SSRI’s (Paroxetine, Fluoxetine(+/-)) • SNRI (Velafaxine (+/-)) • Gabapentin • Clonidine (+/-)

  24. Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Placebo 0.625 CEE 0.625 CEE/2.5 MPA Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79.

  25. Complementary Approaches • May be effective • Black Cohosh • Soy/Phytoestrogens • Vitamin E (1 hot flash per day less) • No evidence • Dong quai • Acupuncture • Yoga • Chinese herbs • Evening primrose • Ginseng • Kava • Red Clover Abstract

  26. Sleep and Mood Disturbances • Vasomotor episodes have an adverse impact on quality of sleep • Sleep disturbances lead to a reduced ability to hand problems and stresses • Women with a history of depression are at risk of reoccurrence during menopause • HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression

  27. Cognition • Lack of agreement on impact of menopause on cognition • No clear evidence that HRT prevents cognitive aging or enhances cognitive function • Vascular infarcts associated with estrogen may worsen dementia in women over 65

  28. Metabolic Changes with Menopause

  29. Mechanisms of Menopause-Related Increases in Adiposity Preferential abdominal fat accumulation Increased abdominal and intra-abdominal adiposity Hormonal changes of the menopause transition Increased fat accumulation Alteredenergy metabolism

  30. “The Menopausal Metabolic Syndrome” • Lipid Triad • Hypertriglyceridemia •  LDL Cholesterol • Abnormalities in Insulin • Insulin resistance •  insulin elimination • HT reduces onset of DM and improves insulin resistance • Other Factors • Endothelial dysfunction •  visceral fat •  uric acid •  HDL Cholesterol •  insulin secretion • Hyperinsulinemia •  SHBG •  blood pressure •  PAI-1

  31. Cardiovascular Disease

  32. Men 500 Women 400 No. X 103 300 200 100 0 29-44 45-64 >65 Age, years Annual Incidence of Myocardial Infarction in Women and Men in the U.S.

  33. Hormone Replacement Therapy and CAHD • Secondary Prevention of CAHD • HERS (Heart and Estrogen/progestin Replacement Study) • No Benefit • Primary Prevention of CAHD • WHI (Women’s Health Initiative) • No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause

  34. Osteoporosis

  35. Pathogenesis of Estrogen Deficiency and Bone Loss • Estrogen loss triggers increases in IL-1, IL-6, and TNF. • Increased cytokines lead to increased osteoclast development and lifespan. • Increased turnover of osteoblasts. • Impacts vitamin D metabolism • Impacts on renal and intestinal handling of calcium

  36. Consequences of Osteoporosis • Spinal (vertebral) compression fractures • Back pain • Loss of height and mobility • Postural deformities • Colles’ (forearm) fractures • Hip Fractures • Tooth loss

  37. Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions When to Measure BMD in Postmenopausal Women One or more risk factors

  38. Prevention of Osteoporosis • Calcium • 1500mg elemental Calcium daily • One serving of dairy=300mg • Supplements (citrate, carbonate) • Divided doses • With meals • Vitamin D supplementation • Sunshine • 400 IU/daily • Weight bearing exercise • Smoking cessation • Moderation of alcohol intake • Pharmacologic • (generally not recommended) • HRT • Raloxifene • Bisphosphonates

  39. Treatment of Osteoporosis (for prevention of fractures) • First Line Agents • Bisphosphonates • Raloxifene • Second Line Agents • Human recombinant PTH • Nasal salmon calcitonin • HRT • Fall prevention strategies

  40. Changes in the UrogenitalSystem

  41. Physiologic Changes in the Urogenital System • Decrease in production of vaginal lubricating fluid • Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) • Development of uretheral caruncles • Mucosal thinning of urethra and bladder

  42. Vaginal Atrophy

  43. Urogenital symptoms • Dysuria • Urgency • Frequency • Recurrent UTIs • Dysparunia • Pruritus • Stenosis • Treatment • Vaginal estrogen (progestogen not necessary) • HRT *

  44. Hormone Replacement Therapy Benefits • Decrease hot flashes • Prevents/treats osteoporosis and hip and vertebral fractures • Prevents/treats urogenital atrophy

  45. Hormone Replacement Therapy Risks • Increased risk for venous thrombosis and embolism** • Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) • Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration

  46. Hormone Replacement Therapy Areas of Concern • Possible increase in cardiac events in older women started on EPT (not ET) • Probably increase in (ischemic) strokes in older women started on HRT

  47. Hormone Replacement Therapy Areas of Concern • Risks are dependent on • Age (total mortality reduced by 30% if started at age <60) • Time since menopause • Age at menopause • Duration of therapy • Type of HT • Route of administration • Dose of HT • Benefits are dependent on • Number of menopause related symptoms

  48. Hormone Therapy Guidelines • Indication: estrogen deficiency symptoms • Vasomotor symptoms • Hot flushes, night sweats • Disturbed sleep patterns • Fatigue, concentration, memory • GU atrophy • Bladder irritability, vaginal dryness, dyspareunia • Guiding principle • Minimum dose for shortest time required • Consider non-hormonal alternatives

  49. Summary of Key Points • Reproductive aging is due to a decline in the number of ovarian follicles. • Menopause • Signals the end of the reproductive years • Diagnosed clinically • Not a disease • Symptoms are due to estrogen deficiency.

  50. Key Points • CAD • Rise in risk probably due to metabolic changes • HRT not indicated for prevention or treatment at this time • Osteoporosis • Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) • Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation • Primary treatment: Raloxifene, Bisphosphonates

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